The presence of two cyclooxygenase isoenzymes, cyclooxygenase-I (COX-I) and cyclooxygenase-II (COX-II) is known (Proc. Nat. Acad. Sci. USA 88, 2692-2696 (1991)).
Traditional non steroidal anti-inflammatory compounds (NSAIDs) have inhibiting activities of both COX-I and COX-II (J. Biol. Chem., 268, 6610-6614 (1993), etc). The therapeutic use thereof involves undesired effects on the gastrointestinal tract, such as bleeding, erosions, gastric and intestinal ulcers, etc.
It was reported that selective inhibition of COX-II shows anti-inflammatory and analgesic activities comparable with conventional NSAIDs but with a lower incidence of some gastrointestinal undesired effects (Pro. Nat. Acad. Sci. USA, 91, 3228-3232(1994)). Accordingly, various selective COX-II inhibitors have been prepared. However, it was reported that those “selective COX-II inhibitor” show some side-effects on kidney and/or insufficient efficacy on acute pains.
Further, some compounds such as SC-560, mofezolac, etc, which have certain selective inhibiting activity against COX-I. WO98/57910 shows some compounds having such activity. However, their selectivity of inhibiting COX-I does not seem to be enough to use them as a clinically acceptable and satisfactory analgesic agent due to their gastrointestinal disorders.
WO02/055502 shows some pyridine derivatives having cyclooxygenase inhibiting activity, particularly cyclooxygenase-I inhibiting activity. And WO99/51580 shows some triazole derivatives having an inhibiting activity of cytokine production.